Project Summary/Abstract Alzheimer?s Disease (AD) is a massive economic and social burden and is one of the most feared diseases of late life. No treatments that halt or reverse the disease exist. There are several critical gaps in our current knowledge of the molecular and cellular mechanisms that drive AD. Critically, the proximal cause remains unknown. Our long-term goals are to discover the temporal order of changes that take place during disease progression to identify novel ways to treat the disease. Extensive studies of AD in many labs have revealed a complex picture of dysfunction in the brain. The characteristics of the disease result from neurons dying, but before neurodegeneration many molecular and metabolic changes are observed. One dominant hypothesis for AD has centered on one of these changes, the accumulation of neurotoxic protein species (Ab and tau). However, other features, such as an apparent ?energy crisis,? may accompany or even precede neurotoxic protein build-up. To determine the causes and the effects, we propose to study multiple systems affected by the disease simultaneously. We will employ a chemical tool which, based on strong preliminary evidence, induces autophagy, a cellular damage defense mechanism. This chemical (known as C1) modulates both the action of neurotoxic proteins and enhances mitochondrial function, making it a powerful tool to examine the interconnectedness of areas of dysfunction. We now propose four specific aims to advance our understanding of AD as follows: (1) determine the effects of the induction of autophagy by C1 in AD models in the invertebrate nematode worm C. elegans; the worm ages rapidly, allowing the disease to be modelled very efficiently in a contracted time period, (2) determine what energetic and metabolic dysfunction occurs and in what temporal order in AD C. elegans models, (3) determine the effect of the disease on protein abundance and protein aggregation, a hallmark of the disease; the effects of autophagy induction by C1 will also be tested in Aims 2 and 3, and (4) identify the global interplay between these biological systems to uncover the critical changes that occur during disease progression that drive the disorder. Collectively, our proposed research will impact AD research by identifying proximal causes of the disease and providing novel targets for pre-clinical and clinical science. If successful, this ?systems? level approach may be applied to other neurological diseases and other chronic conditions. !